Phosphodiesterases (PDE) play an important role in various biological processes by hydrolyzing the key second messengers adenosine and guanosine 3′,5′-cyclic monophosphates (cAMP and cGMP, respectively) into their corresponding 5′-monophosphate nucleotides. Therefore, inhibition of PDE activity produces an increase of cAMP and cGMP intracellular levels that activate specific protein phosphorylation pathways involved in a variety of functional responses.
At least 11 isoenzymes of mammalian cyclic nucleotide phosphodiesterases, numbered PDE1 through PDE11 , have been identified on the basis of primary structure, substrate specificity, or sensitivity to cofactors or inhibitory drugs.
Among these phosphodiesterases, PDE 7 is a cAMP-specific PDE. The biochemical and pharmacological characterization showed a high-affinity cAMP-specific PDE (Km=0.2 μM), that was not affected by cGMP potent selective PDE isoenzyme inhibitors.
PDE 7 activity or protein has been detected in T-cell lines, B-cell lines, airway epithelial (AE) cell lines, and several fetal tissues.
Increasing cAMP levels by selective PDE7 inhibition appears to be a potentially promising approach to specifically block T-cell mediated immune responses. Further studies have demonstrated that elevation of intracellular cAMP levels can modulate inflammatory and immunological processes. This selective approach could presumably be devoid of the side effects associated with known selective inhibitors (eg, PDE3 or PDE4 selective inhibitors) and which limit their use.
A functional role of PDE7 in T-cell activation has also been disclosed; therefore selective PDE7 inhibitors would be candidates for the treatment of T-cell-related diseases.
AE cells actively participate in inflammatory airway diseases by liberating mediators such as arachidonate metabolites and cytokines. Selective inhibition of PDE7 may be a useful anti-inflammatory approach for treating AE cells related diseases.
Thus, there is a need for selective PDE7 inhibitors, which are active at very low concentrations, ie, micromolar inhibitor, preferably nanomolar inhibitors.